—  SHORT COURSE #26  —

Lung Biopsy Interpretation

Case 1 - Usual Interstitial Pneumonia (UIP)

Anna-Luise A. Katzenstein & Jeffrey L. Myers


Clinical History
This 73 year old man complained of increasing dyspnea and dry cough for two years. He currently is unable to walk more than a few feet without becoming dyspneic. Rales were noted bilaterally on physical examination and there was evidence of early clubbing. Pulmonary function tests showed severe restrictive defects. Chest x-ray and CT showed bilateral interstitial reticular opacities worse at the bases with foci of subpleural honey-comb change. An open lung biopsy was performed.

Microscopic Description:


Case 1 - Figure 1 - Low magnification view showing an interstitial process with distinctly non-uniform appearance. There are alternating zones of alveolar septal fibrosis, inflammation and normal lung.
Case 1 - Figure 2 - Another area from the same slide composed of end-stage, honey-comb lung.


Case 1 - Figure 3 - The area in this photo contains prominent interstitial inflammation and fibrosis within which a small, well-delineated, lightly staining fibroblast focus is visible.
Case 1 - Figure 4 - Higher magnification of fibroblast focus shown in Figure 3. This lesion is an aggregate of oval to spindle-shaped fibroblasts and myofibroblasts arranged with their long axes parallel to the long axis of the alveolar septum. They are embedded in lightly staining, myxoid appearing stroma.

This slide shows extensive interstitial scarring composed of dense collagen deposition and associated mild chronic inflammation. Areas of microscopic honey-comb change are prominent and are characterized by enlarged airspaces lined mainly by bronchiolar epithelium and filled with a mucinous and proteinaceous exudate containing varying numbers of inflammatory cells. The changes have a strikingly heterogeneous, non-uniform appearance at low magnification with islands of relatively normal lung interspersed among the abnormal fibrotic zones. Small areas of active fibrosis (fibroblast foci) are also seen along the interstitium. These foci are composed of spindle-shaped fibroblasts and myofibroblasts within lightly staining, myxoid appearing stroma arranged with their long axis parallel to the long axis of the alveolar septa. The finding of fibroblast foci in a background of inactive appearing collagen type fibrosis indicates temporal heterogeneity.

Discussion: The current classification of the idiopathic interstitial pneumonias includes four entities outlined in Table 1, and the main clinical and pathologic features of these diseases are contrasted in Tables 2 and 3. UIP is the most common idiopathic interstitial pneumonia, comprising over 60% of cases, and idiopathic pulmonary fibrosis (IPF) and cryptogenic fibrosing alveolitis (CFA) are synonyms for this disease. The importance of this classification is to separate the acute (AIP) and the chronic interstitial pneumonias, and in the latter group to separate the poor prognosis (UIP) from the good prognosis (DIP, NSIP) diseases. The possibility that interferon gamma may be beneficial in UIP cases, as well as the development of new therapeutic agents aimed at stopping the fibrosing process, has added additional impetus to precisely classify these entities.

The histologic classification of the idiopathic interstitial pneumonias is usually straightforward. UIP is recognized by a temporally and spatially variegated interstitial fibrosing process. Spatial variegation is recognized at low magnification by a patchwork arrangement of interstitial collagen-type fibrosis, fibroblast foci, interstitial inflammation, microscopic honey-comb change, and normal lung. Architectural distortion typified by honey-comb change or interstitial scarring or both is usually a prominent feature. Temporal variegation is characterized by the presence of active, on-going areas of fibrosis (fibroblast foci) in a background of old, inactive fibrosis (collagen and honey-comb areas). That is, there is evidence of active ongoing disease as well as inactive scarring from previous disease. Fibroblast foci represent microscopic areas of acute lung injury, and they are the earliest histologic manifestation of UIP. The pathogenesis UIP appears to be related to the occurrence of these microscopic foci of acute lung injury in widely scattered portions of lung over many years.

Clinically, UIP usually affects middle aged to older adults, and the disease is uncommon under the age of 40. Men are affected about twice as often as women. The onset is insidious with dry cough and gradually increasing shortness of breath, and the course is relentlessly progressive with death due to respiratory failure occurring in most patients after 2 to 5 years. There is no known effective therapy, although promising results have been described recently with interferon gamma.

The main lesion in the differential diagnosis of UIP is the fibrosing variant of NSIP. The two main histologic features that separate UIP from fibrotic NSIP include the presence of a patchwork pattern of parenchymal involvement and significant architectural distortion. Interestingly, small foci resembling NSIP (so-called NSIP-like areas) are commonly found in otherwise typical UIP cases (a situation analogous to DIP-like areas in UIP), and, therefore, in order to diagnose NSIP the process should be uniform everywhere with little if any architectural distortion.

The following are helpful guidelines in evaluating the idiopathic interstitial pneumonias:

Be cautious about diagnosing UIP when
  the patient is under 40 years old
  microscopic honey-comb change is absent
  inflammation is prominent microscopically
Do not diagnose NSIP when significant architectural distortion is present
Use the clinical history to avoid mistakes
  the presence of a radiographically localized infiltrate excludes UIP and other idiopathic interstitial pneumonias
  rapid (within days) course and systemic symptoms (fever) exclude UIP
  active fibroblast proliferation in patients who are not on a ventilator probably is not AIP (consider BOOP)
Not all lung biopsy specimens will be classifiable into one of the 4 idiopathic interstitial pneumonias. Cases composed entirely of end-stage fibrotic or honey-comb lung should be diagnosed descriptively rather than attempting to pigeon-hole them into a specific category.

Table 1. Classification of Idiopathic Interstitial Pneumonia

Usual Interstitial Pneumonia (UIP)
Desquamative Interstitial Pneumonia (DIP)/Respiratory Bronchiolitis
        Interstitial Lung Disease (RBILD)
Acute Interstitial Pneumonia (AIP, Hamman-Rich disease)
Non-Specific Interstitial Pneumonia (NSIP)

Table 2. Contrasting Clinical Features of the Idiopathic Interstitial Pneumonias

  UIP* DIP/RBILD** AIP*** NSIP****
Male/Female 2.1/1 1.75/1 1/1 1/1.3
Average Age (Range) 57 (27-77) 45 (16-75), DIP36 (22-53), RBILD 49 (7-77) 52 (9-78)
Onset Insidious Insidious Acute Insidious / Subacute
Fever No No Common Common
HRCT Bilateral reticular opacities, peripheral and basilar predom- inance, subpleural honeycombing Ground glass opacity, lower lung and subpleural, irregular lines Air-space consolidation and ground glass opacity Ground glass opacity, usually lower lobes
Course Slowly progressive Chronic Fulminant (1 to 2 months) Chronic to subacute
Outcome 71% (51-93%) mortality 27% mortality (DIP), 0% mortality (RBILD) 62% (50-88%) mortality 12.5% (0- 29%) mortality §

* Data from Crystal, Carrington, Katzenstein (1986), Guerry-Force, Wells, Cherniack, Bjoraker, Daniil, Nagai, Travis, Flaherty (2002)

** Data from Liebow (1965), Gaensler, Patchefsky, Tubbs, Carrington, Myers (1987), Yousem, Travis, Flaherty (2002)

*** Data from Katzenstein (1986), Olsen, Primack

**** Data from Katzenstein (1994), Park, Bjoraker, Daniil, Nagai, Cottin, Flaherty (2002)

§ Mortality rates are the average of reported mortality rates in major series (range of reported rates in parenthesis). The results of Travis et al's and Nicholson et al's series are not included because they appear to lump UIP cases with fibrotic NSIP cases, and the subsequent mortality rates are considerably higher than other series (35% 10 year survival and 45% 5 year survival, respectively)

Table 3. Contrasting Pathologic Features of the Idiopathic Interstitial Pneumonias

  UIP DIP/RBILD AIP NSIP
Distribution of changes Patchy, non-uniform (patch-work pattern) Diffuse (DIP)/ patchy(RBILD), uniform Diffuse, uniform Diffuse, uniform
Temporal appearance Variegated Uniform Uniform Uniform
Alveolar septal inflammation Scant, patchy Scant Scant Prominent
Collagen type fibrosis Characteristic, patchy Variable, diffuse Absent Variable, diffuse
Fibroblast proliferation Fibroblast foci Absent Diffuse Rare fibroblast foci
Intraalveolar macrophage accumulation Occasional, focal Diffuse (DIP) or peribronchiolar (RBILD) No Occasional, focal
Microscopic honey- comb change Characteristic Usually absent No Usually absent
Hyaline membranes Absent Absent Occasional, focal Absent

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